Oxa- and thia-steroids

ABSTRACT

16-Oxa- and 16-thia-D-homo-estrogen derivatives useful as postcoital oral contraceptives which are produced by total synthesis from 1-vinyltetralin-1-ols or their thiuronium derivatives on reactions with 4-substituted tetrahydropyran- or tetrahydrothiopyran-3,5-diones, and subsequent appropriate modifications.

The present invention relates to novel type of oxa- and thia-steroids.More particularly, it relates to 16-oxa- and16-thia-D-homo-1,3,5(10),8,14-estrapentaenes represented by the generalformula (I): ##STR1## wherein R¹ represents a lower alkyl of 1 - 5carbon atoms, R² represents a hydrogen atom or lower alkyl of 1 - 5carbon atoms, R³ and R⁴, one of them represents a hydroxy or acyloxy of1 - 5 carbon atoms, and the other represents a hydrogen atom, loweralkyl of 1 - 5 carbon atoms, ethynyl or aralkyl of 7 - 8 carbon atoms,or taken together, may represent an oxo group, and X represents anoxygen atom or sulfur atom.

More specifically, said compounds may be represented by the generalformulae (Ia), (Ib) and (Ic). ##STR2## wherein R¹, R² and X each has thesame meaning as mentioned above, R⁵ represents a hydrogen atom or acylof 1 - 5 carbon atoms, and R⁶ represents a lower alkyl of 1 - 5 carbonatoms, ethynyl or aralkyl of 7 - 8 carbon atoms.

Large doses of estrogens administered postcoitally to women are known toprevent pregnancy. For example, synthetic estrogens such asethynylestradiol, mestranol and stilbesterol have been used clinicallyas postcoital anti-fertility agents. The use of these estrogens,however, is accompanied by some serious adverse reactions attributableto the estrogenicity of the compounds, for example, nausea, vomiting,menorrhagia, altered cycle length, breast soreness, insomnia, etc. It isdesirable accordingly to develop new anti-fertility agents in which theanti-fertility action is separated from the estrogenicity.

The present inventors have succeeded in producing a novel type ofestrogens having potent anti-implantational activity but lessestrogenicity.

In the aforementioned general formulae, the lower alkyl indicated by R¹,R², R³, R⁴ and R⁶ includes methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, i-butyl, t-butyl, n-pentyl, 2-methylbutyl, i-pentyl, t-pentyl,and the like. The acyloxy indicated by R³ and R⁴ includes alkanoyloxy of1 - 5 carbon atoms, as for example acetoxy, propionyloxy, butyryloxy,i-butyryloxy, valeryloxy, i-valeryloxy, and the like. The aralkylindicated by R³, R⁴ and R⁶ includes benzyl, phenethyl, and the like. Theacyl indicated by R⁵ includes alkanoyl of 1 - 5 carbon atoms, as forexample acetyl, propionyl, butyryl, i-butyryl, valeryl, i-valeryl, andthe like.

Representative of the objective compounds (I) are:

3-Hydroxy-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17a-one,

3-Hydroxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one,

3-Methoxy-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17a-one,

3-Methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one,

3-Methoxy-18-methyl-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17a-one,

3-Methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one,

18-Ethyl-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one,

3-Ethoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one,

3-Methoxy-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol,

3-Methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol,

16-Thia-D-homo-1,3,5(10),8,14-estrapentaene-3,17aα-diol,

3-Methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol,

3-Methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol

3-Methoxy-18-i-propyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol,

18-n-Butyl-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol,

18-Methyl-3-n-propoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol,

3-Valeryloxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol,

3-Methoxy-17aβ-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a.alpha.-ol,

3-Methoxy-17aα-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a.beta.-ol,

17aβ-Ethyl-3-methoxy-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17a.alpha.-ol,

3-Methoxy-17aβ-n-pentyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol,

17aβ-Benzyl-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a.alpha.-ol,

3-Methoxy-17aα-phenethyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol,

17aβ-Benzyl-3-methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol,

17aβ,18-Dimethyl-3-ethoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol,

17aβ-ethynyl-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a.alpha.-ol,

3-Methoxy-17aα-ethynyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol,

17aβ-Ethynyl-3-methoxy-18-methyl-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol,

17aα-Acetoxy-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaene, and

17aβ-Acetoxy-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaene.

The objective compounds (I) as mentioned above may be prepared from1-vinyltetralin-1-ols (IIa) or their thiuronium derivatives (IIb) onreaction with 4-substituted tetrahydropyran- ortetrahydrothiopyran-3,5-diones (III) as illustrated in the followingreaction scheme. ##STR3## (wherein R¹, R², R⁵, R⁶, and X eachindependently has the same meaning as defined above).

The starting compounds (IIa) and (IIb) used in the invention are knownand have been described in, for example, S. N. Ananchenko and I. V.Torgov, Chem.Abstr., 54, 1599 (1960); C. H. Kuo, D. Taub and N. L.Wendler, Angew.Chem., 77, 1142 (1965).

The reaction of the 1-vinyltetralin-1-ols (IIa) or their thiuroniumderivatives (IIb) with the tetrahydropyran- ortetrahydrothiopyran-3,5-diones (III) to the tetracyclic compounds (Ia)may be effected substantially according to the method developed byTorgov or its modification in estrogen syntheses [Jean Weill-Raynal,Bull.soc.chim.France, 1969, 4561].

The condensation of the 1-vinyltetralin-1-ols (IIa) with the diones(III) may be carried out in the presence of a basic catalyst, ifrequired in an organic solvent under heating. The basic catalystsapplicable to this condensation include inorganic bases such as alkalimetal hydroxides (e.g. sodium hydroxide, potassium hydroxide) or alkalimetal carbonates (e.g. sodium carbonate, potassium carbonate, lithiumcarbonate), organic bases such as alkali metal acetates (e.g. sodiumacetate, potassium acetate), alkali metal alkoxides (e.g. sodiummethoxide, potassium methoxide, sodium ethoxide, potassium ethoxide,potassium t-butoxide), quaternary ammonium hydroxides (e.g. Triton B =benzylmethylammonium hydroxide), basic solvents (e.g. pyridine,collidine) or other catalysts (e.g. anion exchange resins, alumina). Theorganic solvents include alkanols (e.g. methanol, ethanol, isopropanol,n-butanol, t-butanol, isoamyl alcohol), ethers (e.g. ethyl ether,tetrahydrofuran, dioxane, glyme, diglyme), aromatic hydrocarbons (e.g.benzene, toluene, xylene), and the above-mentioned basic solvents ascatalysts. The reaction may be conducted at approximately 50° C orhigher temperatures, while removing the water produced in the course ofthe reaction or in the presence of a drying agent such as molecularsieves (Union Carbide, F, MCB, Davison Division of W. R. Grace and Co.),in order to accelerate the reaction.

The condensation of the thiuronium derivatives (IIb) with the diones(III) may be carried out in an aqueous solution at temperatures rangingfrom room temperature to approximately 60° C. The aqueous solution meanswater or a mixture of water and an organic solvent, preferablywater-miscible organic solvent such as alkanol (e.g. methanol, ethanol,isopropanol), ether (e.g. tetrahydrofuran, dioxane, glyme),dimethylsulfoxide, dimethylformamide, or the like.

The subsequent cyclization of the resulting compounds (IV) to thetetracyclic compounds (Ia) is effected in an organic solvent at anelevated temperature in the presence of an acid catalyst or dehydratingagent. The acid catalysts or dehydrating agents preferably used includeorganic acids (e.g. formic acid, acetic acid, benzenesulfonic acid,p-toluenesulfonic acid, 2,4-dinitrobenzenesulfonic acid), inorganicacids (e.g. hydrochloric acid, perchloric acid, sulfuric acid,phosphoric acid and/or phosphorous pentoxide), and acid resins. Theorganic solvents used include lower alkanols (e.g. methanol, ethanol,propanol), halogeno hydrocarbons (e.g. methylene chloride, chloroform,ethylene chloride), aliphatic carboxylic acids (e.g. acetic acid,propionic acid), esters (e.g. ethyl acetate), and aromatic hydrocarbons(e.g. benzene, toluene, xylene). For example, when the reaction isconducted in an aromatic hydrocarbon, the water produced during thereaction can be eliminated as azeotropic mixture from the reactionmedium. In such a case, the reaction may preferably be conducted at therefluxing temperature of the solvent used, accordingly.

The conversion of the 17a-oxo compounds (Ia) to the 17a-hydroxycompounds (Ib: R⁵ = H) may be achieved by reducing agents or appropriatereduction methods applicable to the reduction of carbonyl group. Thepreferred reducing agents include so-called complex metal hydrides, e.g.lithium aluminium hydride, lithium tri-t-butoxy aluminium hydride,lithium tri-methoxy aluminium hydride, sodium aluminium hydride, sodiumborohydride, lithium borohydride, potassium borohydride, zincborohydride, sodium bis(2-methoxyethoxy)aluminium hydride. The reductionby these reducing agents may be carried out in the conventional manneraccording to the property of each reducing agent. For example, thereduction by lithium aluminium hydride may be conducted in an etherealsolvent, e.g. ethyl ether, tetrahydrofuran, glyme, at an appropriatetemperature such as the refluxing temperature of the solvent used. Thereduction by sodium borohydride may be conducted in a proper solventwhich may contain water, e.g. methanol, ethanol, i-propanol,tetrahydrofuran, dioxane, glyme, diglyme, at room temperature, ifrequired at an elevated temperature.

The acyl derivatives (Ib: R⁵ = acyl) of the 17a-hydroxy compounds (Ib:R⁵ = H) may be produced by acylation with acylating agents such as acylhalides (e.g. acetyl chloride, propionyl chloride, valeryl chloride),acid anhydrides (e.g. acetic anhydride, i-valeryl anhydride), mixedanhydrides (e.g. mixed anhydrides prepared from acetic acid and ethylchloroformate, from acetic anhydride and formic acid or from acetylchloride and sodium formate), combinations of aliphatic carboxylic acids(e.g. acetic acid, propionic acid, valeric acid) and acid catalysts(e.g. p-toluenesulfonic acid), and the like in a conventional manner.

The production of the 17a-substituted derivatives (Ic) from the 17a-oxocompounds (Ia) may be effected according to the general procedures foralkylation, ethynylation and aralkylation of carbonyl compounds.

The alkylation and the aralkylation each may be carried out by means ofalkylating agents or aralkylating agents such as alkyl- oraralkyl-magnesium halides (so-called Grignard agents; e.g.methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium bromide,n-propylmagnesium chloride, benzylmagnesium bromide, phenethylmagnesiumbromide), and other organometallic compounds involving alkali metalcompounds (e.g. methyllithium, ethylsodium, i-propyllithium). Thereaction is usually carried out in an aprotic solvent, particularlyethereal solvent, e.g. ethyl ether, tetrahydrofuran, glyme, diglyme, inanhydrous condition at a temperature ranging from room temperature tothe refluxing temperature of the solvent used. The reaction temperatureand time may be fixed according to the reactivity of the reactants.

The ethynylation of the 17-a-oxo compounds (Ia) may be carried out inthe conventional manner for ethynylation of carbonyl compounds, forexample, by ethynylating agents such as acetylene magnesium halides(e.g. ethynylmagnesium bromide), ethynylmagnesium chloride) or alkalimetal acetylides (e.g. sodium acetylide, lithium acetylide, potassiumacetylide) prepared from acetylene and alkali metals, appropriate bases(e.g. potassium hydroxide, potassium t-butoxide, potassium t-amyloxide)or alkali metal hydrides (e.g. lithium aluminium hydride). The reactionsmay usually be conducted in liquid ammonia, ethylenediamine, ethylamine,aniline, dimethylacetamide, hexametapol (HMPT), ethereal solvents (e.g.ethyl ether, tetrahydrofuran, dioxane) or aromatic hydrocarbons (e.g.benzene, toluene, xylene), at a variable temperatures, if required underpressure.

The other starting compounds (III) used in the present invention arenovel and may be prepared from commercially available compounds asillustrated in the following reaction scheme. ##STR4## (wherein Yrepresents a halogen atom, R⁷ represents an ester residue, and R¹ and Xeach independently has the same meaning as defined above).

The reactions illustrated in the above reaction sequence may be effectedin the well-known conventional manners.

The thus resulting objective compounds (I), as mentioned above, have apotent anti-implantational activity and less estrogenicity, and may beused as postcoital contraceptive. The estrogenic activity andanti-implantational activity of the compounds of the present inventionwere compared with those of a commercially available known estrogen,mestranol. The following table indicates the assay data.

                  Table                                                           ______________________________________                                                            Anti-implantational                                                                          Ratio of                                   Compound                                                                              Estrogenicity                                                                             Activity       AI/E                                       ______________________________________                                        Mestranol                                                                             100         100            1.0                                        A       12          40             3.3                                        B       12          100            8.3                                        C       22          400            18                                         D       3.7         100            27                                         E       3.6         100            28                                         F       0.84        40             48                                         G       1.3         100            76                                         ______________________________________                                         Remark:                                                                       AI/E = anti-implantational activity/estrogenicity                             A = 3-Methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one (Ia:         R.sup.1 = R.sup.2 = Me; X = S)                                                B = 3-Methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol        (Ib: R.sup.1 = R.sup.2 = Me; OR.sup.5 = α-OH; X = S)?                   C = 16-Thia-D-homo-1,3,5(10),8,14-estrapentaene-3,17aα-diol (Ib:        R.sup.1 = Me; R.sup.2 = H; OR.sup.5 = α-OH; X = S)?                     D =                                                                           3-Methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-    l (Ib: R.sup.1 = Et; R.sup.2 = Me; OR.sup.5 = β-OH; X = S)                E =                                                                           3-Methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα    ol (Ib: R.sup.1 = Et; R.sup.2 = Me; OR.sup.5 = α-OH; X =  S)             F =                                                                           17aβ-Ethynyl-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17    α-ol (Ic: R.sup.1 = R.sup.2 = Me; R.sup.6 = β-C.tbd.CH; X = S)      G = 3-Methoxy-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol (Ib:     R.sup.1 = R.sup.2 = Me; OR.sup.5 = β-OH; X = O)                     

Test for Estrogenicity (Vaginal TTC Reduction)

Female albino mice of DS colony were used through the experiments. Theanimals were overiectomized at 29 to 33 days of age under methylhexabital sodium anesthesia. Ten days after the castration, the testcompounds were orally administered through a sonde as a solutiondissolved in 0.1 ml of sesame oil. After the lapse of 27 hours, anaqueous solution of 2,3,5-triphenyltetrazolium chloride (TTC) (1 mg/20μl) was injected into the vaginae, and after 30 minutes the animals wereautopsied. The vaginae were isolated, and the formazan formed in thevagina during 30 minutes was quantitatively analyzed by a colorimetricmethod. The relative potency of the compounds to mestranol wascalculated by means of 4-point assay or 6-point assay.

Test for Anti-implantation

Adult female rats of the Wistar strain, weighing 150 g to 200 g, weremated with intact adult male rats. The day on which sperm was found invagina was designated as Day 1 of pregnancy. A suspension of the testcompounds suspended in an aqueous vehicle (consisting of 0.4%polysorvate, 0.5% carboxymethylcellulose, 0.9% benzyl alcohol and 0.9%sodium chloride) was orally administered through a sonde once a day for6 days, and the animals were laparotomized on Day 8 in order to countthe number of implantation sites in both uterine horns. Autopsy was madeon Day 15 to count the number of placental sites or scars, fetuses andcorpora lutea. The amount of the test compounds administered wasincreased until no implantation was observed in all animals. Therelative potency of the compounds to mestranol was calculated from theminimum amount by which the implantation was inhibited.

In the above table, the respective values of estrogenicity andanti-implantational activity were fixed as relative potency when thoseof mestranol were regarded as 100.

In addition of these activities, the compounds (I) of the presentinvention have cholesterol-lowering action, and may also be used ascholesterol lowering agents, accordingly.

When the compounds of the present invention are employed as postcoitaloral contraceptives, they may be formulated with suitable excipients inthe form of tablets or capsules for oral administration and may beadministered within a period of 48 hours after the coition in single ordivided doses containing 0.1 - 4.0 mg a day for more than 4 days.

The invention will be better explained by the following examples whichare not intended as a limitaion thereof.

In this specification, the numbering of steroidal nucleus and theindication of the α- or β-configuration are designated according to therules of IUPAC nomenclature system.

EXAMPLE 1 ##STR5## (a)3-Methoxy-8(14)-seco-16-thia-D-homo-1,3,5(10),9(11)-estratetraene-14,17a-dione(IV: R¹ =R² =Me; X=S)

To a stirred mixture of 32.2 g (0.1 mole) of the isothiurnium acetate(IIb: R² =Me) and 14.4 g (0.1 mole) of4-methyltetrahydrothiopyran-3,5-dione is added 500 ml of 50% aqueousalcohol. A clear solution is observed within 5 minutes followed byprecipitation of the product after an additional 5 minutes. The reactionmixture is stirred at room temperature for 3 hours. After standingovernight in a refrigerator, the precipitate is filtered, washed withcold aqueous alcohol and then air-dried to give 28.0 g (84.8% yield) ofthe dione (IV: R¹ =R² =Me; X = S), mp. 91.5° - 92.5° C.Recrystallization from methylene chloride - ether gives an analyticalspecimen, mp. 93° - 94° C. IR: ν_(max) ^(Nujol) cm⁻¹ : 1727, 1691, 1604,1573, 1496. UV: λ_(max) ^(EtOH) mμ (ε): 267 (18100), 300 (5600;shoulder). NMR: ppm (CDCl₃): 1.38 (singlet, 3H, 13-Me), 3.36 and 3.50(quartet, 4H, J = 14.5, SCH₂ CO), 3.76 (singlet, 3H, OMe), 5.62 (broadtriplet, 1H, J = 7.5, 11-H), 6.60 - 7.49 (multiplet, 3H, aromaticprotons). Anal. Calcd. for C₁₉ H₂₂ O₃ S (%): C, 69.06; H, 6.71; S, 9.70.Found (%): C, 68.90; H, 6.66; S, 9.84.

The following compounds can be prepared in the same manner as mentionedabove.

3-Methoxy-18-methyl-8(14)-seco-16-thia-D-homo-1,3,5(10),9(11)-estratetraene-14,17a-dione(IV: R¹ =Et; R² =Me; X = S): mp. 72°-72.5° C (recrystallized fromether - pentane). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1722, 1693, 1606,1568, 1493. UV: λ_(max) ^(EtOH) mμ (ε): 267 (17000), 300 (4900;shoulder). NMR: ppm (CDCl₃): 0.83 (triplet, 3H, J = 7.5, 18-Me), 3.78(singlet, 3H, OMe), 5.66 (broad triplet, 1H, J = 7.5, 11-H), 6.62 - 7.50(multiplet, 3H, aromatic protons). Anal. Calcd. for C₂₀ H₂₄ O₃ S (%): C,69.73; H, 7.02; S, 9.31. Found (%): C, 69.55; H, 6.98; S, 9.47.

3-Methoxy-8(14)-seco-16-oxa-D-homo-1,3,5(10),9(11)-estratetraene-14,17a-dione(IV: R¹ =R² =Me; X=O): mp. 143°-144° C (recrystallized from methylenechloride - ether). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1744, 1714, 1605,1569, 1497. UV: λ_(max) ^(EtOH) mμ (ε): 268 (16000), 300 (5100;shoulder). NMR: ppm (CDCl₃): 1.36 (singlet, 3H, 13-Me), 3.78 (singlet,3H, OMe), 4.18 and 4.34 (quartet, 4H, J = 18, OCH₂ CO), 5.64 (broadtriplet, 1H, J = 7.5, 11-H), 6.60 - 7.49 (multiplet, 3H, aromaticprotons). Anal. Calcd. for C₁₉ H₂₂ O₄ (%): C, 72.59; H, 7.05. Found (%):C, 72.38; H, 7.08.

3-Methoxy-18-methyl-8(14)-seco-16-oxo-D-homo-1,3,5(10),9(11)-estratetraene-14,17a-dione(IV: R¹ =Et; R² =Me; X=O): mp. 60.5° - 61° C (recrystallized frommethanol). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1740, 1711, 1605, 1567,1493. UV: λ_(max) ^(EtOH) mμ (ε): 267.5 (15800), 300 mμ (4600;shoulder). NMR: ppm (CDCl₃): 0.83 (triplet, 3H, J = 7.5, 18-Me), 3.77(singlet, 3H, OMe), 4.19 (singlet, 4H, OCH₂ CO), 5.62 (broad triplet,1H, J = 8.0, 11-H), 6.60 - 7.48 (multiplet, 3H, aromatic protons). Anal.Calcd. for C₂₀ H₂₄ O₄ : (%): C, 73.14; H, 7.37. Found (%): C, 72.88; H,7.40.

(b) 3-Methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one (Ia: R¹= R² =Me; X = S)

A solution of 6.6 g (20 mmole) of3-methoxy-8(14)-seco-16-thia-D-homo-1,3,5(10),8,14-estratetraene-14,17a-dionein 100 ml of dry benzene containing 300 mg of p-toluenesulfonic acidmonohydrate is heated under refluxing for 10 minutes. The cooledsolution is poured into water, and the benzene layer is separated. Theaqueous layer is extracted with ether, and the organic layers arecombined, washed with an aqueous sodium bicarbonate solution and anaqueous sodium chloride solution, and dried over anhydrous sodiumsulfate. The solvent is evaporated in vacuo to give a gummy residue,which is adsorbed on 30 g of neutral alumina and elutated with benzene.The eluates are collected, the solvent evaporated, and the residue iscrystallized from methylene chloride - ether to give 5.78 g (92.7%yield) of the objective tetracyclic pentaene (Ia: R¹ =R² =Me; X = S),mp. 94°-96° C. Recrystallization from the same solvents affords ananalytical specimen, mp. 95° - 96° C. IR: ν _(max) ^(CHCl).sbsp.3 cm⁻¹ :1705, 1608, 1563, 1496. UV: λ_(max) ^(EtOH) mμ (ε): 320 (27500;shoulder), 333 (33000), 345 (25500; shoulder). NMR: ppm (CDCl₃): 1.37(singlet, 3H, 13-Me), 3.37 and 3.51 (quartet, 2H, J = 14.0, SCH₂ CO),3.80 (singlet, 3H, OMe), 6.37 (broad singlet, 1H, 15-H), 6.69 - 7.32(multiplet, 3H, aromatic protons). Anal. Calcd. for C₁₉ H₂₀ O₂ S (%): C,73.04; H, 6.45; S, 10.26. Found (%): C, 73.29; H, 6.51; S, 10.58.

The following compounds can be prepared in the same manner as mentionedabove.

3-Methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one(Ia: R¹ =Et; R² =Me; X = S): mp. 105.5°-106.5° C (recrystallized fromether). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1703, 1608, 1561, 1493. UV:λ_(max) ^(EtOH) mμ (ε): 320 (25000; shoulder), 332 (29900), 345 (23500;shoulder). NMR: ppm (CDCl₃): 0.80 (triplet, 3H, J = 7.5, 18-Me), 3.40(singlet, 2H, SCH₂ CO), 3.79 (singlet, 3H, OMe), 6.38 (broad singlet,1H, 15-H), 6,64 - 7.28 (multiplet, 3H, aromatic protons). Anal. Calcd.for C₂₀ H₂₂ O₂ S (%): C, 73.58; H, 6.79; S, 9.82. Found (%): C, 73.37;H, 6.71; S, 10.01.

3-Methoxy-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17a-one (Ia: R¹ =R²=Me; X = O): mp. 113° - 115° C (recrystallized from methylene chloride -ether). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1721, 1618, 1604, 1563, 1495.UV: λ_(max) ^(EtOH) mμ (ε): 301 (23500; shoulder), 313.5 (28200), 327(20100; shoulder). NMR: ppm (CDCl₃): 1.28 (singlet, 3H, 13-Me), 3.80(singlet, 3H, OMe), 4.20 and 4.61 (quartet, 2H, J = 18, OCH₂ CO), 6.83(singlet, 1H, 15-H), 6.68 - 7.29 (multiplet, 3H, aromatic protons).Anal. Calcd. for C₁₉ H₂₀ O₃ (%): C, 77.00; H, 6.80. Found (%): C, 76.73;H, 6.69.

3-Methoxy-18-methyl-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17a-one(Ia: R¹ =Et; R² =Me; X = O): mp. 63° - 64.5° C (recrystallized fromether - pentane). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1715, 1617, 1604,1563, 1494. UV: λ_(max) ^(EtOH) mμ (ε): 301 (23400; shoulder), 313.5(28200), 327 (19500; shoulder). NMR: ppm (CDCl₃): 0.84 (triplet, 3H, J =7.5, 18-Me), 3.79 (singlet, 3H, OMe), 4.19 and 4.46 (quartet, 2H, J =18, OCH₂ CO), 6.88 (singlet, 1H, 15-H), 6.68 - 7.26 (multiplet, 3H,aromatic protons). Anal. Calcd. for C₂₀ H₂₂ O₃ (%): C, 77.39; H, 7.14.Found (%): C, 77.07; H, 7.12.

EXAMPLE 2 ##STR6##3-Methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-ols (Ib: R¹ =R²=Me; R⁵ =H; X = S)

Sodium borohydride (115 mg; 3.04 mmole) is added portionwise to anice-cold stirred suspension of 312.4 mg (1 mmole) of3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one in 10 ml ofmethanol. The suspension turns into a clear solution in a few minutesand then another suspension after 20 minutes. The suspension is stirredat room temperature for 2 hours. The pH is adjusted to 7 with about 0.2ml of concentrated hydrochloric acid under cooling, and ice-cold wateris added thereto. The reaction mixture is extracted with methylenechloride, and the extract is washed with an aqueous sodium chloridesolution and dried over anhydrous sodium sulfate. Removal of the solventleaves a viscous syrup (323 mg), which is purified by preparative thinlayer chromatography using silica gel and benzene - ethyl acetate (9 :1). The upper band gives 212 mg (67.4% yield) of the 17aα-ol, which iscrystallized from methylene chloride - ether to give 198.7 mg (63.2%yield) of crystals, mp. 140° - 143° C. Recrystallization from methylenechloride - acetone gives the analytical specimen, mp. 140° - 142° C. IR:ν_(max) ^(CCl).sbsp.4 cm⁻¹ : 3553. UV: λ_(max) ^(EtOH) mμ (ε): 318(30800; shoulder), 329.5 (40400), 345 (30800). NMR: ppm (CDCl₃): 0.99(singlet, 3H, 13-Me), 3.78 (singlet, 3H, OMe), 6.13 (broad singlet, 1H,15-H), 6.66 - 7.30 (multiplet, 3H, aromatic protons). Anal. Calcd. forC₁₉ H₂₂ O₂ S (%): C, 72.57; H, 7.05; S, 10.20. Found (%): C, 72.39; H,7.04; S, 10.22.

On the other hand, the lower band gives 87.8 mg (27.9% yield) of the17aβ-ol, which is crystallized from ether - petroleum ether to give 86.1mg (27.4%) of crystals, mp. 139° - 141° C. Recrystallization fromacetone - ether gives the analytical specimen, mp. 140° - 141° C. IR:ν_(max) ^(CCl).sbsp.4 cm⁻¹ : 3632. UV: λ_(max) ^(EtOH) mμ (ε): 317(30400; shoulder), 329 (39700), 343.5 (30400). NMR: ppm (CDCl₃): 1.02(singlet, 3H, 13-Me), 3.78 (singlet, 3H, OMe), 6.02 (broad singlet, 1H,15-H), 6.65 - 7.29 (multiplet, 3H, aromatic protons). Anal. Calcd. forC₁₉ H₂₂ O₂ S (%): C, 72.57; H, 7.05; S, 10.20. Found (%): C, 72.21; H,7.03; S, 10.24.

The product ratio of the 17aα-ol to the 17aβ-ol is 2.4 to 1.0.

The corresponding acetates (Ib: R¹ =R² Me; R⁵ =Ac; X = S) are preparedby acetylation using acetic anhydride and pyridine.

17aα-Acetate: mp. 136° - 137° C (crystallized from ether - petroleumether). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1728, 1608, 1560, 1486, 1254.UV: ν_(max) ^(EtOH) mμ (ε): 315 (31400, shoulder), 328.5 (41500), 343.5(31300). NMR: ppm (CDCl₃): 1.07 (singlet, 3H, 13-Me), 2.10 (singlet, 3H,OCOMe), 3.80 (singlet, 3H, OMe), 4.98 (triplet, 1H, J = 3, 17aβ-H), 6.21(broad singlet, 1H, 15-H), 6.68 - 7.31 (multiplet, 3H, aromaticprotons). Anal. Calcd. for C₂₁ H₂₄ O₃ S (%): C, 70.75; H, 6.79; S, 9.00.Found (%): C, 70.92; H, 6.88; S, 9.03.

17aβ-Acetate: mp. 162.5° - 164° C (crystallized from methylenechloride - ether). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1744, 1729, 1607,1559, 1496, 1250. UV: λ_(max) ^(EtOH) mμ (ε): 315 (29900; shoulder), 328(39200), 343 (30600). NMR: ppm (CDCl₃): 1.10 (singlet, 3H, 13-Me), 2.10(singlet, 3H, OCOMe), 3.79 (singlet, 3H, OMe), 5.06 (quartet, 1H, J =5.0 and 10.5, 17aα-H), 6.06 (broad singlet, 1H, 15-H), 6.68 - 7.30(multiplet, 3H, aromatic protons). Anal. Calcd. for C₂₁ H₂₄ O₃ S (%): C,70.75; H, 6.79; S, 9.00. Found(%): C, 70.57; H, 6.81; S, 9.12.

The following compounds can be prepared in the same manner as mentionedabove.

3-Methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol(Ib: R¹ =Et; R² =Me; R⁵ =H; X = S): mp. 112.5° - 114° C (recrystallizedfrom ether - pentane). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1607, 1561,1494; ν_(max) ^(CCl).sbsp.4 cm⁻¹ : 3554. UV: λ_(max) ^(EtOH) mμ (ε): 316(27000; shoulder), 330 (36500), 345 (28000). Anal. Calcd. for C₂₀ H₂₄ O₂S (%): C, 73.13; H, 7.37; S, 9.76. Found (%): C, 72.91; H, 7.34; S,9.79.

3-Methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol(Ib: R¹ =Et; R² =Me; R⁵ =H; X = S)-: mp. 100° - 101.5° C (recrystallizedfrom ether - pentane). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1607, 1563,1494; ν_(max) ^(CCl).sbsp.4 cm⁻¹ : 3631. UV: λ_(max) ^(EtOH) mμ (ε): 315(27700; shoulder), 329.5 (37500), 344 (27900). NMR: ppm (CDCl₃): 0.96(triplet, 3H, J = 7.0, 18-Me), 3.79 (singlet, 3H, OMe), 6.06 (singlet,1H, 15-H), 6.66 - 7.29 (multiplet, 3H, aromatic protons). Anal. Calcd.for C₂₀ H₂₄ O₂ S (%): C.73.13; H. 7.37; S, 9.76. Found (%): C, 72.88; H,7.35; S, 10.01.

3-Methoxy-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol (Ib: R¹ =R²=ME; R⁵ =H; X = O): mp. 140.5° - 142° C (recrystallized from methylenechloride - ether). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1618, 1563, 1493;ν_(max) ^(CCl).sbsp.4 cm⁻¹ : 3633, 3613 (shoulder). UV: λ_(max) ^(EtOH)mμ (ε): 299 (23000; shoulder), 311 (27900), 323 (21300; shoulder). Anal.Calcd. for C₁₉ H₂₂ O₃ (%): C, 76.48; H, 7.43. Found (%): C, 76.27; H,7.45.

17aβ-Acetoxy-3-methoxy-16-oxa-D-homo-1,3,5(10),8,14-estrapentaene (Ib:R¹ =R² =Me; R⁵ =Ac; X = O): mp. 161° - 164° C (recrystallized frommethylene chloride - ether). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1736,1620, 1563, 1493, 1243. NMR: ppm (CDCl₃): 1.13 (singlet, 3H, 13-Me),2.11 (singlet, 3H, OCOMe), 3.79 (singlet, 3H, OMe), 5.00 (quartet, 1H, J= 5 and 10, 17aα-H), 6.58 (broad singlet, 1H, 15-H), 6.67 - 7.27(multiplet, 3H, aromatic protons).

3-Methoxy-18-methyl-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol(Ib: R¹ =Et; R² =Me; R⁵ =H; X = O): mp. 105.5° - 107° C (recrystallizedfrom ether - pentane). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1620, 1564,1495; ν_(max) ^(CCl).sbsp.4 cm⁻¹ : 3632. UV: λ_(max) ^(EtOH) mμ (ε): 300(23700; shoulder), 312.2 (28300), 324 (21500; shoulder). NMR: ppm(CDCl₃): 0.94 (triplet, 3H, J = 7.5, 18-Me), 3.79 (singlet, 3H, OMe),6.61 (broad singlet, 1H, 15-H), 6.65 - 7.24 (multiplet, 3H, aromaticprotons). Anal. Calcd. for C₂₀ H₂₄ O₃ (%): C, 76.89; H, 7.74. Found (%):C, 76.67; H, 7.83.

16-Thia-D-homo-1,3,5(10),8,14-estrapentaene-3,17aβ-diol (Ib: R¹ = Me; R²=R⁵ =H; X = S)

Ethanethiol (625 mg; 10 mmole), dissolved in 10 ml of drydimethylformamide, is added to a suspension of 500 mg (10.5 mmole) of50% sodium hydride in mineral oil in 5 ml of dry dimethylformamide undernitrogen, and the mixture is stirred for 5 minutes. A solution of 500 mg(1.59 mmole) of3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol in 5 ml ofdry dimethylformamide is added therein, and the solution is refluxed for1.5 hours. The cooled mixture is acidified with an aqueous hydrochloricacid solution and extracted with chloroform - methanol (9 : 1). Theorganic layer is washed with an aqueous sodium chloride solution, driedover anhydrous sodium sulfate and evaporated in vacuo. Trituration withmethylene chloride gives 417.9 mg of the 3-ol as crystalline solid, mp.224° - 227° C.

The mother liquor residue is purified by passing through a short columnof silica gel and eluating with petroleum ether - benzene and then withmethylene chloride to give 8.1 mg of an additional crop, mp. 220° - 225°C. Total yield is 426.0 mg (89.2%). Recrystallization from methylenechloride gives the analytical specimen, mp. 231° - 234° C. IR: ν_(max)^(KBr) cm⁻¹ : 3427, 3312, 1604, 1572, 1552, 1499. UV: λ_(max) ^(EtOH) mμ(ε): 315 (33900; shoulder), 328.5 (44200), 343 (33600). NMR: ppm (d₆-DMSO): 0.92 (singlet, 3H, 13-Me), 5.12 (multiplet, 1H, J = 10, 17aα-H),6.10 (broad singlet, 1H, 15-H), 6.54 - 7.20 (multiplet, 3H, aromaticprotons). Anal. Calcd. for C₁₈ H₂₀ O₂ S(%): C, 71.96; H, 6.71; S, 10.67.Found (%): C, 71.78; H, 6.63; S, 10.33.

The following compound can be prepared in the same manner as mentionedabove.

16-Thia-D-homo-1,3,5(10),8,14-estrapentaene-3,17aα-diol (Ib: R¹ =Me; R²=R⁵ =H; X = S): mp. 197° - 198.5° C (recrystallized from methanol -methylene chloride). IR: ν_(max) ^(KBr) cm⁻¹ : 3406, 3236, 1608, 1601,1566, 1498. UV: λ_(max) ^(EtOH) mμ (ε): 317 (28200; shoulder), 329(36900), 345 (27800).; NMR: ppm (d₆ -DMSO): 0.88 (singlet, 3H, 13-Me),4.66 (broad doublet, 1H, J = 5.0, 17aβ-H), 6.16 (broad singlet, 1H,15H), 6.53 - 7.18 (multiplet, 3H, aromatic protons). Anal. Calcd. forC₁₈ H₂₀ O₂ S (%): C, 71.96; H, 6.71; S, 10.67. Found (%): C, 71.68; H,6.74; S, 10.47.

EXAMPLE 3 ##STR7##3-Methoxy-17a-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-ols(Ic: R¹ =R² =R⁶ =Me; X = S)

A Grignard reagent (MeMgI) is prepared from 7.45 g (52.5 mmole) ofmethyl iodide, 1.24 g (51.2 mg atom) of magnesium and a total of 40 mlof dry ether. To the ice-cold Grignard solution is slowly added withstirring a solution of 2.0 g (6.4 mmole) of3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one in 40 ml ofdry tetrahydrofuran, and the mixture is stirred at room temperature for7 hours. The mixture is then cooled and hydrolyzed with an ice-coldsolution of ammonium chloride, the organic layer is separated, and theaqueous layer is extracted with ether - methylene chloride (3 : 1). Theorganic layers are combined, washed with an aqueous sodium chloridesolution, dried over anhydrous sodium sulfate, and evaporated in vacuo.The crude product is checked by thin layer chromatography, which showsapproximately half of the starting material still remaining unchanged.Thus, the crude product is repeatedly treated with an additional 25.6mmole of methyl magnesium iodide and worked up in the same manner asmentioned above. The finally resultant residue is purified bypreparative thin layer chromatography using silica gel and benzene-ethylacetate (9 : 1).

The upper band gives 867 mg (43.3% yield) of the starting material.

The middle band gives 599 mg (50.3% yield) of the 17aα-ol (Ic: R¹ =R²=Me; R⁶ =β-Me; X = S), which is crystallized from ether to give 565.2 mgof crystals, mp. 183° - 184° C. Recrystallization from methylenechloride - ether gives the pure analytical specimen, mp. 183.5 - 184.5°C. IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1607, 1561, 1492; ν_(max)^(CCl).sbsp.4 cm⁻¹ : 3554. UV: λ_(max) ^(EtOH) mμ (ε): 316 (27700;shoulder), 330 (36500), 344 (27800; shoulder). NMR: ppm (CDCl₃): 1.04(singlet, 3H, 13-Me), 1.36 (singlet, 3H, 17aβ-Me), 3.78 (singlet, 3H,OMe), 6.19 (broad singlet, 1H, 15-H), 6.66 - 7.29 (multiplet, 3H,aromatic protons). Anal. Calcd. for C₂₀ H₂₄ O₂ S (%): C, 73.13; H, 7.37;S, 9.76. Found (%): C, 72.84; H, 7.35; S, 9.66.

The lower band gives 416.9 mg (35.0% yield) of the 17aβ-ol (Ic: R¹ =R²=Me; R⁶ =α-Me; X = S), which is crystallized from ether - pentane togive 357.1 mg of crystals, mp. 152° - 156° C. Recrystallization frommethylene chloride - ether gives the analytical specimen, mp. 153° -155° C. IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1608, 1560, 1492; ν_(max)^(CCl).sbsp.4 cm⁻¹ : 3618. UV: λ_(max) ^(EtOh) mμ (ε): 316 (24500;shoulder), 330 (32900), 345 (25500). NMR: ppm (CDCl₃): 1.08 (singlet,3H, 13-Me), 1.40 (singlet, 3H, 17aα-Me), 3.78 (singlet, 3H, OMe), 6.02(broad singlet, 1H, 15-H), 6.66 - 7.29 (multiplet, 3H, aromaticprotons). Anal. Calcd. for C.sub. 20 H₂₄ O₂ S (%): C, 73.13; H, 7.37; S,9.76. Found (%): C, 72.89; H, 7.36; S, 10.03.

17a-Ethynyl-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-ols(Ic: R¹ =R² =Me; R⁶ =C.tbd.CH; X = S)

A solution of 2.0 g (6.4 mmole) of3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one in 130 mlof dry tetrahydrofuran and a solution of 2.0 g of potassium in 30 ml ofdry t-amyl alcohol are added with stirring to 130 ml of drytetrahydrofuran saturated with purified acetylene gas over a period ofabout 1 hour. Stirring is continued at room temperature for 6 hours withcontinuous bubbling of acetylene. Finally, the reaction mixturesaturated with acetylene is kept at 0° C in a refrigerator overnight andthen decomposed with an aqueous ammonium chloride solution. Extractionwith ether - methylene chloride (3 : 1) followed by usual work-up givesthe crude product (1.89 g), which is purified by preparative thin layerchromatography using silica gel and benzene-ethyl acetate (20 : 1)

The upper band gives 1.296 g (59.8% yield) of the 17aα-ol, (Ic: R¹ = R²= Me; R⁶ = 17aβ-C.tbd.CH; X = S), which is crystallized from methylenechloride - ether to give 1.26 g of crystalline product, mp. 173.5° -174° C. IR: ν_(max) ^(Nujol) cm⁻¹ : 2100, 1608, 1597, 1561, 1496;ν_(max) ^(CC1).sbsp.4 cm⁻¹ : 3540. UV: λ_(max) ^(EtOH) mμ (ε): 316(28200; shoulder), 329.5 (37700), 345 (28800). NMR: ppm (C₅ D₅ N): 1.30(singlet, 3H, 13-Me), 3.40 (singlet, 1H, C.tbd.CH), 3.73 (singlet, 3H,OMe), 6.40 (broad singlet, 1H, 15-H). Anal. Calcd. for C₂₁ H₂₂ O₂ S (%):C, 74.52; H, 6.55; S, 9.47. Found (%): C, 74.28; H, 6.47; S, 9.22.

The lower band gives 0.108 g (5.0%) of the 17aβ-ol, which iscrystallized from tetrahydrofuran - ether to give 84.9 mg of acrystalline product, mp. 214° - 216° C. IR: ν_(max) ^(Nujol) cm⁻¹ :2100, 1603, 1595, 1495, 1552; ν_(max) ^(CCl).sbsp.4 cm⁻¹ : 3612. UV:λ_(max) ^(EtOH) mμ (ε): 316 (28400; shoulder), 329.5 (38200), 345(29400). NMR: ppm (C₅ D₅ N): 1.33 (singlet, 3H, 13-Me), 3.23 (singlet,1H, C.tbd.CH), 3.73 (singlet, 3H, OMe), 6.37 (broad singlet, 1H, 15-H).Anal. Calcd. for C₂₁ H₂₂ O₂ S (%): C, 74.52; H, 6.55; S, 9.47. Found(%): C, 74.21; H, 6.53; S, 9.29.

17a-Benzyl-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-ols(Ic: R.sup. 1 = R² = Me; R⁶ = CH₂ Ph; X = S)

To an ice-cold Grignard reagent preliminarily prepared from 9.21 g (53.9mmole) of benzyl bromide, 1.26 g (51.9 mg atom) of magnesium, 15 ml ofdry ether and 10 ml of dry tetrahydrofuran is dropwise added withstirring a solution of 2.08 g (6.66 mmole) of3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one in 15 ml ofdry tetrahydrofuran. The mixture is stirred at room temperature for 13hours and then refluxed for 7 hours followed by standing overnight.Usual work-up gives an oily residue (8.8 g), which contains a largeamount of a non-polar compound to be presumed as 1,2-diphenylmethane.This is spearated by passing through a column of 30 g of neutral aluminaand eluating with petroleum ether, petroleum ether - benzene (9 : 1),petroleum ether- benzene (1 : 1), benzene, benzene - methylene chloride(1 : 1), and methylene chloride, successively.

The fractions of from petroleum ether to benzene - methylene chloride (1: 1) are further separated by thin layer chromatography (silica gel;benzene-n-hexane (1 : 1)). The upper band gives 450.8 mg (21.7%) of thestarting ketone, the middle band 346.1 mg of the 17aα-ol, and the lowerband 42.5 mg of the 17aβ-ol.

Thin layer chromatography (silica gel; benzene) of the above methylenechloride fraction gives an additional 287 mg of the 17aα-ol and 278.7 mgof the 17aβ-ol. Total yields of the 17aα-ol and the 17aβ-ol were 633.1mg (30.1%) and 321.2 mg (15.2%) respectively.

These compounds have the following physical properties.

The 17aα-ol (Ic: R¹ = R² = Me; R⁶ = β-CH₂ Ph; X = S): mp. 155° - 157° C(recrystallized from carbon tetrachloride - ether). IR: ν_(max)^(CHC1).sbsp.3 cm⁻¹ : 1606, 1561, 1493; λ_(max) ^(CCl).sbsp.4 cm⁻¹ :3553. UV: ν_(max) ^(EtOH) mμ (ε): 316 (26700; shoulder), 330 (35300),345 (27000; shoulder). NMR: ppm (CDCl₃): 1.14 (singlet, 3H, 13-Me), 3.79(singlet, 3H, OMe), 6.20 (broad singlet, 1H, 15-H), 6.67 - 7.30(multiplet, 8H, aromatic protons). Anal. Calcd. for C₂₆ H₂₈ O₂ S (%): C,77.19; H, 6.98; S, 7.93. Found (%): C, 77.08; H, 6.91; S, 7.74.

The 17aβ-ol (Ic: R¹ = R² = Me; R⁶ = α-CH₂ Ph; X = S): mp. 143° - 144.5°C (recrystallized from carbon tetrachloride - ether). IR: ν_(max)^(CHCl).sbsp.3 cm⁻¹ : 1608, 1561, 1494; ν_(max) ^(CCl).sbsp.4 cm⁻¹ :3611, 3580. UV: λ_(max) ^(EtOH) mμ (ε): 317 (27400; shoulder), 331(37800), 346.5 (28900). NMR: ppm (CDCl₃): 1.15 (singlet, 3H, 13-Me),3.78 (singlet, 3H, OMe), 6.13 (broad singlet, 1H, 15-H), 6.67 - 7.50(multiplet, 8H, aromatic protons). Anal. Calcd. for C₂₆ H₂₈ O₂ S (%): C,77.19; H, 6.98; S, 7.93. Found (%): C, 76.93; H, 6.93; S, 7.80.

EXAMPLE 4 ##STR8##

The starting diglycolic anhydride and thiodiacetic anhydride may beprepared from commercially available diglycolic acid and thiodiaceticacid [H. L. Morrill et al., J.Org.Chem., 26, 4103 (1961)]

(a) Methyl 2-(chloroformylmethylmercapto)acetate

A mixture of 82.8 g (0.63 mole) of thiodiacetic anhydride and 20.2 g(0.63 mole) of methanol is heated at 60° - 70° C under stirring for 1hour. To the resulting homogeneous liquid, 91 ml (1.25 mole) of thionylchloride is added dropwise while hydrogen chloride and sulfur dioxideevolved are continuously trapped through an aqueous sodium hydroxidesolution. The solution is allowed to stand at room temperature overnightuntil no gas evolved. The excess amount of thionyl chloride is removedunder reduced pressure and the residual liquid is fractionally distilledto give 105.8 g (92.4% yield) of the acid chloride, bp. 129° - 130° C/17mmHg. This is purified by redistillation to give 99.0 g (86.5% yield) ofthe pure material, bp. 125° - 126° C/13 mmHg. IR: ν_(max) ^(Neat) cm⁻¹ :1800, 1740; ν_(max) ^(CHCl).sbsp.3 cm¹ : 1797, 1742. NMR: ppm (CDCl₃):3.38 (singlet, 2H, CH₂ COO), 3.75 (singlet, 3H, COOMe), 3.93 (singlet,2H, CH₂ COCl). Anal. Calcd. for C₅ H₇ O₃ SCl (%): C, 32.88; H, 3.86; S,17.56. Found (%): C, 32.68; H, 3.88; S, 17.40.

(b) Methyl 2-(3-methylacetonylmercapto)acetate

To a stirred ice-cold ethereal Grignard solution (392 ml) containing0.56 mole of ethylmagnesium bromide, is added 51.3 g (0.28 mole) of drypowdered cadmium chloride in small portions. Stirring is continuedwithout heating for 5 minutes, followed by refluxing for 30 - 45 minutesuntil no Gilman test for Grignard reagent is observed. Then, 500 ml ofdry benzene is added thereto, and the resulting cadmium reagent iscooled to below 0° C (usually -10° to 0° C). A solution of 91.3 g (0.5mole) of methyl 2-(chloroformylmethylmercapto)acetate in 500 ml of drybenzene is added with vigorous stirring as rapidly as consistent withcontrol of the exothermic reaction. The reaction mixture is stirred atroom temperature for 3 - 5 hours, then decomposed by addition of cold 6Nsulfuric acid, and extracted three times with ether. The organicextracts are combined, washed successively with an aqueous sodiumbicarbonate solution and an aqueous sodium chloride solution and driedover sodium sulfate. After evaporation of the solvent in vacuo, theresidual liquid is distilled under reduced pressure to give 53.7 g(60.9% yield) of methyl 2-(3-methylacetonylmercapto)acetate as an oilymaterial, bp. 137 - 140° C/13 mmHg). IR: ν_(max) ^(Neat) cm⁻¹ : 1740,1711; ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1737, 1712. NMR: ppm (CDCl₃): 1.10(triplet, 3H, J = 7, CH₂ CH₃), 2.62 (quartet, 2H, J = 7, CH₂ CH₃), 3.28(singlet, 2H, SCH₂ COO), 3.43 (singlet, 2H, SCH₂ CO), 3.73 (singlet, 3H,COOMe). Anal. Calcd. for C₇ H₁₂ O₃ S (%): C, 47.70; H, 6.86; S, 18.19.Found (%): C, 47.96; H, 6.98; S, 17.90.

(c) 4-Methyltetrahydrothiopyran-3,5-dione (III: R¹ = Me; X = S)

A solution of 101.3 g (0.57 mole) of methyl2-(3-methylacetonylmercapto)acetate in 2.3 liter of dry tetrahydrofuranis added dropwise over a period of 3 hours to a stirred suspension of0.57 mole of sodium hydride (27.4 g of 50% mineral oil suspension) in1.1 liter of dry tetrahydrofuran at room temperature under nitrogen.Stirring is continued for an additional 3 hours. The resulting yellowreaction mixture is concentrated to a small volume at temperature below40° C under reduced pressure, poured into ice-cold water and thenextracted with ether. The aqueous layer is acidified at pH 2 - 3 withdilute hydrochloric acid and extracted several times with chloroform.The extracts are washed with a small portion of an aqueous sodiumchloride solution and dried over anhydrous sodium sulfate. The solventis removed in vacuo and the residue is crystallized from methylenechloride - ether to give 62.7 g (75.6% yield) of4-methyltetrahydrothiopyran-3,5-dione, mp. 131° - 133° C.Recrystallization from acetone - ether gives an analytical specimen, mp.132.5 - 133° C. IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1735, 1705, 1631;ν_(max) ^(Nujol) cm⁻¹ : 1635, 1553. UV: λ_(max) ⁹⁵ %EtOH mμ (ε): 275(9500), 315 (2400); λ_(max) ^(N--HCl) mμ (ε): 272 (9900); μ_(max)^(N--NaOH) mμ (ε): 289 (11600), 316 (12900). NMR: ppm (CDCl₃): 1.28(doublet, 3H, J = 7, Me), 3.44 (singlet, 4H, 2-H₂ and 6-H₂), 3.73(quartet, 1H, J = 7, 4-H); ppm (CD₃ OD): 1.69 (broad singlet, 3H,vinyl-Me), 3.34 (broad singlet, 4H, 2-H₂ and 6-H₂). Anal. Calcd. for C₆H₈ O₂ S (%): C, 49.98; H, 5.59; S, 22.24. Found (%): C, 50.17; H, 5.50;S, 22.14.

The following compounds can be prepared in the same manner as mentionedabove.

4-Ethyltetrahydrothiopyran-3,5-dione (III: R¹ = Et; X = S): mp. 108.5° -109.5° C (recrystallized from methylene chloride - ether). IR: ν_(max)^(CHCl).sbsp.3 cm⁻¹ : 1736, 1703, 1623; ν_(max) ^(Nujol) cm⁻¹ : 1570.UV: λ_(max) ⁹⁵ %EtOH mμ (ε): 273 (9600), 317 (1200). NMR: ppm (CDCl₃):0.95 (triplet, 3H, J = 7.5, Me), 1.93 (quintet, 2H, J = 7.5, CH₂ CH₃),3.41 (singlet, 4H, 2-H₂ and 6-H₂); ppm (CD₃ OD): 0.92 (triplet, 3H, J =7.5, Me), 1.84 (broad quartet, 0.42H, J = 7.5, CH₂ Ch₃), 2.32 (quartet,1.58H, J = 7.5, vinyl CH₂ CH₃), 3.34 (singlet, 4H, 2-H₂ and 6-H₂). Anal.Calcd. for C₇ H₁₀ O₂ S (%): C, 53.14; H, 6.27; S, 20.27. Found (%): C,53.07; H, 6.35; S, 20.18.

4-Methyltetrahydropyran-3,5-dione (III: R¹ = Me; X = O): mp. 178° - 180°C (recrystallized from chloroform containing a small amount ofmethanol). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1755, 1725, 1642; λ_(max)^(Nujol) cm⁻¹ : 1653, 1570. UV: ν_(max) ⁹⁵ %EtOH mμ (ε): 261.5 (15700),291 (4000; shoulder). NMR: ppm (CDCl₃ -- CD₃ OH = 98 : 2): 1.26(doublet, 0.825H, J = 7, Me), 1.74 (broad singlet, 2.175H, vinyl Me),4.21 (broad singlet, 4H, 2-H₂ and 6-H₂); ppm (CD₃ OD): 1.70 (broadsinglet, 3H, vinyl Me), 4.18 (broad singlet, 4H, 2-H₂ and 6-H₂). Anal.Calcd. for C₆ H₈ O₃ (%): C, 56.24; H, 6.29. Found (%): C, 56.36; H,6.37.

4-Ethyltetrahydropyran-3,5-dione (III: R¹ = Et; X = O): mp. 117° - 119°C (recrystallized from methylene chloride - ether). IR: ν_(max)^(CHCl).sbsp.3 cm⁻¹ : 1756, 1721, 1626; ν_(max) ^(Nujol) cm⁻¹ : 1617(shoulder), 1570. UV: λ_(max) ^(95%EtOH) mμ (ε): 261.5 (12200). NMR: ppm(CDCl₃): 1.01 (triplet, 3H, J = 8, Me), 1.85 (quintet, 0.28H, J = 7 - 8,CH₂ CH₃), 2.35 (quartet, 1.72H, J = 8, vinyl CH₂), 4.27 (singlet, 4H,2-H₂ and 6-H₂). Anal. Calcd. for C₇ H₁₀ O₃ (%): C, 59.14; H, 7.09. Found(%): C, 58.80; H, 7.03.

We claim:
 1. A compound of the general formula: ##STR9## wherein R¹represents a lower alkyl of 1 - 5 carbon atoms, R² represents a hydrogenatom or lower alkyl of 1 - 5 carbon atoms, R³ and R⁴, one of themrepresents a hydroxy or alkanoyloxy of 1 - 5 carbon atoms, and the otherrepresents a hydrogen atom, lower alkyl of 1 - 5 carbon atoms, ethynylor aralkyl of 7 - 8 carbon atoms, or taken together, may represent anoxo group, and X represents an oxygen atom or sulfur atom.
 2. A compoundof the general formula: ##STR10## wherein R¹ represents a lower alkyl of1 - 5 carbon atoms, R² represents a hydrogen atom or lower alkyl of 1 -5 carbon atoms, and X represents an oxygen atom or sulfur atom.
 3. Acompound claimed in claim 2, said compound being3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one.
 4. Acompound claimed in claim 2, said compound being3-methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a-one.5. A compound of the general formula: ##STR11## wherein R¹ represents alower alkyl of 1 - 5 carbon atoms, R² represents a hydrogen atom orlower alkyl of 1 - 5 carbon atoms, and R⁵ represents a hydrogen atom oralkanoyl of 1 - 5 carbon atoms, and X represents an oxygen atom orsulfur atom.
 6. A compound claimed in claim 5, said compound being3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aα-ol.
 7. Acompound claimed in claim 5, said compound being16-thia-D-homo-1,3,5(10),8,14-estrapentaene-3,17aα-diol.
 8. A compoundclaimed in claim 5, said compound being3-methoxy-18-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol.9. A compound claimed in claim 5, said compound being3-methoxy-18-methyl-16-thia-D-homo-1,3,5(10)8,14-estrapentaen-17aα-ol.10. A compound claimed in claim 5, said compound being3-methoxy-16-oxa-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol.
 11. Acompound claimed in claim 5, said compound being17aα-acetoxy-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaene. 12.A compound of the general formula: ##STR12## wherein R¹ represents alower alkyl of 1 - 5 carbon atoms, R² represents a hydrogen atom orlower alkyl of 1 - 5 carbon atoms, R⁶ represents a lower alkyl of 1 - 5carbon atoms, ethynyl or aralkyl of 7 - 8 carbon atoms, and X representsan oxygen atom or sulfur atom.
 13. A compound claimed in claim 12, saidcompound being3-methoxy-17aβ-methyl-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a.alpha.-ol.14. A compound claimed in claim 12, said compound being17aβ-ethyl-3-methoxy-16-oxa-D-homo-1,3,5(10), 8,14-estrapentaen-17aα-ol.15. A compound claimed in claim 12, said compound being17aβ-benzyl-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a.alpha.-ol.16. A compound claimed in claim 12, said compound being17aα-benzyl-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol.17. A compound claimed in claim 12, said compound being17aβ-ethynyl-3methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17a.alpha.-ol.18. A compound claimed in claim 12, said compound being17aα-ethynyl-3-methoxy-16-thia-D-homo-1,3,5(10),8,14-estrapentaen-17aβ-ol.